US6653456B2ExpiredUtilityPatentIndex 63
Site-specific aminoglycoside derivatives and their use in immunodiagnostic assays
Est. expiryJul 31, 2021(expired)· nominal 20-yr term from priority
C07H 5/06C07K 16/44Y10T436/13Y10S530/807G01N 33/9446Y10S435/968C07H 3/06Y10S435/81A61K 31/7008Y10S436/815Y02P20/55
63
PatentIndex Score
1
Cited by
39
References
52
Claims
Abstract
A method of making a derivatized aminoglycoside includes reacting an aminoglycoside with at least 2 equivalents of a divalent metal ion in an aprotic solvent to complex two neighboring amino group and hydroxyl group pairs; reacting the non-complexed amino groups with a protecting reagent to provide protecting groups; removing the divalent metal ion to provide two unprotected amino groups; reacting one of the unprotected amino groups with a reactive substance containing an linker, a carrier, or a label; and removing the protecting groups. This method can be used to produce novel compounds and reagents.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A method of making a derivatized aminoglycoside, comprising:
reacting an aminoglycoside of formula (I) with at least 2 equivalents of a divalent metal ion in an aprotic solvent to complex two neighboring amino group and hydroxyl group pairs;
wherein
A is —CH 2 NH 2 , —CHCH 3 NH 2 , or —CHCH 3 NHCH 3 ;
B is —H or —OH;
D is —H or —OH;
E is —NH 2 or —OH;
G is —NH 2 , or —NHCH 3 ;
J is —H or —OH;
L is —H, —CH 3 , or —OH;
Q is —H or —CH 2 OH; and
Y is —H, or —C(═O)CH(OH)CH 2 CH 2 NH 2 ;
reacting the non-complexed amino groups with a protecting reagent to provide protecting groups;
removing the divalent metal ion to provide two unprotected amino groups;
reacting one of the unprotected amino groups with a reactive substance comprising -T; and
removing the protecting groups to produce a compound of formula (II)
wherein
G′ is —NH 2 , —NHCH 3 , —NH-T, or —NCH 3 -T;
Y′ is —H, —C(═O)CH(OH)CH 2 CH 2 NH 2 , or -T; and
T is a linker, a label, or a carrier, with the proviso that either G′ or Y∝, but not both, comprises -T.
2. The method of claim 1 , wherein the divalent metal ion is selected from the group consisting of Cu 2+ , Co 2+ , Ni 2+ , Zn 2+ , and Cd 2+ .
3. The method of claim 1 , wherein the divalent metal ion is Zn 2+ .
4. The method of claim 1 , wherein the protecting groups comprise an acyl group.
5. The method of claim 1 , wherein the protecting groups comprise tert-butoxycarbonyl.
6. The method of claim 1 , wherein the protecting groups comprise trifluoroacetyl.
7. The method of claim 1 , wherein the removing the divalent metal ion comprises treating the divalent metal ions with ammonium hydroxide.
8. The method of claim 1 , wherein the removing the divalent metal ion comprises treating the divalent metal ions with a precipitating reagent.
9. The method of claim 1 , wherein the reactive substance comprising -T is an acylating agent.
10. The method of claim 1 , further comprising reacting G with a protecting group after the removing the divalent metal ion.
11. The method of claim 10 , wherein
-T is a label of formula (III)
12. The method of claim 1 , wherein
-T comprises a poly(amino acid).
13. The method of claim 1 , wherein
-T comprises an active ester of formula (IV)
14. The method of claim 13 , wherein -T is a moiety of formula (V)
15. The method of claim 1 , wherein
-T comprises aminodextran.
16. The method of claim 15 , wherein -T is a moiety of formula (VI)
17. The method of claim 1 , wherein T is a linker; and wherein the method further comprises
reacting the linker with a label or a carrier.
18. The method of claim 17 , wherein -T comprises from 1 to 20 carbon atoms.
19. The method of claim 18 , wherein -T comprises from 1 to 10 carbon atoms.
20. The method of claim 18 , wherein -T comprises at least one heteroatom.
21. The method of claim 18 , wherein -T comprises at least one cyclic group.
22. The method of claim 17 , wherein the linker and carrier together are —C(═O)—CH 2 CH 2 —C(═O)-poly(amino acid).
23. The method of claim 1 , wherein -T comprises an activating group selected from the group consisting of active ester, isocyanate, isothiocyanate, thiol, imidazolyl, maleimide, carboxylic acid, urea, and biotin.
24. The method of claim 1 , wherein
A is —CH 2 NH 2 ;
B is —H;
D is —H;
E is —NH 2 ;
J is —OH;
L is —H; and
Q is —CH 2 OH.
25. The method of claim 24 , wherein G′ is —NH 2 and Y′ is -T.
26. The method of claim 24 , wherein G′ is —NH-T and Y′ is —H.
27. The method of claim 1 , wherein
A is —CH 2 NH 2 , —CHCH 3 NH 2 , or —CHCH 3 NHCH 3 ;
B is —H;
D is —H;
E is —NH 2 ;
J is —OH;
L is —CH 3 ; and
Q is —H.
28. The method of claim 27 , wherein G′ is —NHCH 3 and Y′ is -T.
29. The method of claim 27 , wherein G′ is —N(CH 3 )-T and Y′ is —H.
30. The method of claim 1 , further comprising reacting one of the unprotected amino groups with a compound of formula (VII) after removing the divalent metal ion
wherein the aminoglycoside is kanamycin; and
wherein A is —CH 2 NH 2 ;
B is —OH
D is —OH;
E is —OH;
G′ is —NH-T;
J is —OH;
L is —H;
Q is —CH 2 OH; and
Y′ is —C(═O)CH(OH)CH 2 CH 2 NH 2 .
31. The method of claim 1 , further comprising isolating the compound together with non-site specific aminoglycoside derivatives;
wherein the purity of the compound is at least 90%.
32. The method of claim 31 , wherein the purity of the compound is at least 95%.
33. The method of claim 31 , wherein the purity of the compound is at least 97%.
34. The method of claim 31 , wherein the purity of the compound is at least 99%.
35. A reagent, comprising:
a compound of formula (II)
wherein
A is —CH 2 NH 2 , —CHCH 3 NH 2 , or —CHCH 3 NHCH 3 ;
B is —H or —OH;
D is —H or —OH;
E is —NH 2 or —OH;
G′ is —NH 2 , —NHCH 3 , —NH-T, or —NCH 3 -T;
J is —H or —OH;
L is —H, —CH 3 , or —OH;
Q is —H or —CH 2 OH; and
Y′ is —H or -T; and
T is a linker, a carrier, or a label, with the proviso that either G′ or Y′, but not both, comprises -T.
36. The reagent of claim 35 , wherein -T comprises a reactive group selected from the group consisting of biotin, thiols, maleimides, isocyanates, isothiocyanates, imidazolyl groups, carboxylic acids, and active esters.
37. The reagent of claim 35 , wherein -T is a label of formula (III)
38. The reagent of claim 35 , wherein -T comprises a poly(amino acid).
39. The reagent of claim 35 , wherein -T comprises an active ester of formula (IV)
40. The reagent of claim 35 , wherein -T comprises aminodextran.
41. A compound of formula (II):
wherein
A is —CH 2 NH 2 , —CHCH 3 NH 2 , or —CHCH 3 NHCH 3 ;
B is —H or —OH;
D is —H or —OH;
E is —NH 2 or —OH;
G′ is —NH 2 , —NHCH 3 , —NH—X, or —NCH 3 —X;
J is —H or —OH;
L is —H, —CH 3 , or —OH;
Q is —H or —CH 2 OH; and
Y′ is —H, —C(═O)CH(OH)CH 2 CH 2 NH 2 , or —X; and
wherein —X is present in only one of G′ or Y′ and is a moiety of formula (VIII), (IX), or (X)
42. The compound of claim 41 , wherein
A is —CH 2 NH 2 ;
B is —H;
D is —H;
E is —NH 2 ;
G′ is —NH 2 ;
J is —OH;
L is —H;
Q is —CH 2 OH; and
Y is —X.
43. The compound of claim 41 , wherein
A is —CH 2 NH 2 ;
B is —H;
D is —H;
E is —NH 2 ;
G′ is —NH—X;
J is —OH;
L is —H;
Q is —CH 2 OH; and
Y′ is —H.
44. The compound of claim 41 , wherein
A is —CH 2 NH 2 , —CHCH 3 NH 2 , or —CHCH 3 NHCH 3 ;
B is —H;
D is —H;
E is —NH 2 ;
G′ is —NHCH 3 ;
J is —OH;
L is —CH 3 ;
Q is —H; and
Y′ is —X.
45. The compound of claim 41 , wherein
A is —CH 2 NH 2 , —CHCH 3 NH 2 , or —CHCH 3 NHCH 3 ;
B is —H;
D is —H;
E is —NH 2 ;
G′ is —N(CH 3 )—X;
J is —OH;
L is —CH 3 ;
Q is —H; and
Y′ is —H.
46. The compound of claim 41 , wherein
A is —CH 2 NH 2 ;
B is —OH;
D is —OH;
E is —OH;
G′ is —NH—X;
J is —OH;
L is —H;
Q is —CH 2 OH; and
Y′ is —C(═O)CH(OH)CH 2 CH 2 NH 2 .
47. A test kit for determining an aminoglycoside analyte in a sample, the kit comprising, in packaged combination, an antibody specific for the analyte and a reagent comprising the compound of claim 41 .
48. A reagent, comprising:
a compound of formula (II)
wherein
A is —CH 2 NH 2 , —CHCH 3 NH 2 , or —CHCH 3 NHCH 3 ;
B is —H or —OH;
D is —H or —OH;
E is —NH 2 or —OH;
G′ is —NH-T;
J is —H or —OH;
L is —H, —CH 3 , or —OH;
Q is —H or —CH 2 OH;
Y′ is —C(═O)CH(OH)CH 2 CH 2 NH 2 ; and
T is a linker, a carrier, or a label.
49. The reagent of claim 48 , wherein -T is a label of formula (III)
50. The reagent of claim 48 , wherein -T comprises a poly(amino acid).
51. The reagent of claim 48 , wherein -T comprises an active ester of formula (IV)
52. The reagent of claim 48 , wherein -T comprises aminodextran.Cited by (0)
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